An experimental therapeutic vaccine did not slow CD4 T-cell decline or enable study participants to safely interrupt antiretroviral therapy (ART) longer, but it did appear to leave HIV viral load at lower levels, researchers reported in the February 11 advance edition of Lancet Infectious Diseases.

Richard Pollard from UC Davis Medical Center and an international team of colleaguesevaluated the safety, efficacy, and immunogenicity of Vacc-4x, a peptide-based therapeutic vaccine targeting conserved domains of HIV-1's Gag p24 protein.

This Phase 2 study, conducted between July 2008 and June 2010, enrolled HIV positive adults at 18 sites in Germany, Italy, Spain, the U.K., and the U.S. The protocol initially called for 345 participants, but only 136 enrolled. At study entry participants were on combination antiretroviral therapy (ART) and had undetectable viral load (<50 copies/mL) and CD4 T-cell counts of at least 400 cells/mm3.

Participants were randomly assigned (2:1) to Vacc-4x or placebo arms, receiving weekly injections for 4 weeks followed by booster shots at weeks 16 and 18. At week 28, they underwent investigational ART interruption for up to 24 weeks. The primary endpoints were need for ART resumption and changes in CD4 counts during treatment interruption. Viral load, immunogenicity (as measured by ELISPOT and proliferation assays), and safety were also assessed.

Results

There were no differences between the Vacc-4x and placebo groups regarding the primary efficacy endpoints.

However, participants in the Vacc-4x group had a significantly lower median viral load both at week 48 (23,100 vs 71,800 copies/mL) and at week 52 (19,550 vs 51,000 copies/mL).

Vacc-4x was found to be immunogenic, inducing proliferative responses in both CD4 and CD8 T-cells.

Finally, Vacc-4x was generally safe and well-tolerated, with only 1 serious adverse event considered possible related to treatment (exacerbation of multiple sclerosis).

"The proportion of participants resuming combination ART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination," the study authors concluded. "Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load set-point reduction after combination ART interruption, and might be worth consideration in future HIV cure investigative strategies."

In an accompanying editorial, Merlin Robb and Jerome Kim from the U.S. Military HIV Research Program discussed the implications of this study for HIV cure-related research, including practical and ethical questions about analytic treatment interruption (ATI).

"Whether future ATI studies will be allowed to progress to set-point or whether an earlier viral-load threshold will trigger reinitiation of combination ART is an important scientific and ethical issue, and one that people on treatment should influence (through community advisory boards)," they wrote. "The challenge of curing an infection that is not sterilized by natural immune responses, with a pathogen integrated into the genome of the host's long-lived, quiescent CD4 T cells is daunting. The suggestion by Pollard and colleagues of the potential for vaccine-induced immune responses to modulate viral set-point during ATI might be an important proof-of-principle and a first tentative step to an effective set of immune interventions."

Below is an edited excerpt from a Bionor press release describing the study and its findings in more detail.

Therapeutic HIV Vaccine, Vacc-4x, Reduced Viral Load in HIV Patients Compared to Placebo in Largest Randomized, Placebo-controlled Study of its Kind in Recent History, Published in Lancet Infectious Diseases

Oslo, Norway -- 11 February 2014 -- Bionor Pharma ASA (OSE: BIONOR) announces that the results from the randomized, multicenter, double-blinded, placebo-controlled Phase II trial with 135 patients of the Company’s lead candidate Vacc-4x will be published in The Lancet Infectious Diseases and is available online at www.thelancet.com as of today.

Therapeutic vaccines for infectious diseases are used in patients who already are infected with the goal of reducing or eliminating the circulating virus. The study showed that in subjects that completed a 6-month interruption of antiretrovirals (ART), there was a log 0.44 (64%) reduction in median viral load set-point in the Vacc-4x group compared to placebo. In addition, the Vacc-4x group showed a statistically significant reduction log 0.4 (60%) in viral load set-point compared to subjects' pre-ART viral load values.

"Researchers are optimistic that the data offers clues for how such a vaccine could be optimized and offer the first new treatment modality in HIV in over coming years," said Richard Pollard, MD, Professor, Chief, Infectious Diseases, University of California Davis. "We need to understand why Vacc-4x appears to have worked much better in some patients than in others, in order to help expedite its regulatory approval."

"The publication of the Vacc-4x results by one of the world’s most prestigious medical journals is an important milestone for Bionor Pharma and Vacc-4x," said Anker Lundemose, MD, PhD, CEO of Bionor Pharma. "We are grateful to the patients around the world who volunteered for this study in order to help build our understanding of how best to optimize this vaccine."

The HIV set-point is the viral load of a person infected with HIV. Viral load is measured as HIV viral RNA copies per ml of blood plasma.

About the Trial

The study was a Phase II randomized, multicenter, double-blind, placebo-controlled multinational clinical trial of Vacc-4x. The trial enrolled 137 patients and was conducted at clinical trial sites in UK, US, Germany, Italy, and Spain between July 2008 and June 2010. The 52-week follow-up period was completed in June 2011. The study is registered with Clinicaltrials.gov with the identifier NCT00659789.

The co-primary endpoints were time to resumption of antiretroviral therapy (cART) and changes in CD4 T-cell counts between Vacc-4x and placebo over time during treatment interruption.

After a 28-week immunization period on cART, eligible patients were taken off cART and monitored for another 24 weeks. cART was resumed if CD4 counts fell below 350 [cells/mm3] or fell by more than 50% of the count at the start of the ART-free period, or if viral load increased above 300,000 copies/ml.

The proportion of participants that resumed cART between interruption of cART at week 28 and the end of the study at week 52 (34.1% Vacc-4x and 28.9% placebo) was not statistically significant (p=0.89). Similarly, the time to return to cART was not different (median 198 days Vacc-4x, 175 days placebo, p=0.77). The percentage change in CD4-counts between the two groups from week 28 to resumption of ART, alternatively week 52 showed a mean treatment difference of -5.71% which was not statistically significant (p=0.12).

Although the study did not meet its primary endpoints, a statistically significant difference in viral load at weeks 48 (median 23,100 copies/mL Vacc-4x (n=59), 71,800 copies/mL placebo (n=25), p=0.025) and 52 (median 19,550 copies/mL Vacc-4x (n=56), 51,000 copies/mL placebo (n=24), p=0.041) between the Vacc-4x and placebo groups was observed. For subjects that completed a 6 month treatment interruption, there was a 64% reduction in median viral load set point between the two groups which was statistically significant (Vacc-4x 22,300 copies/mL, n=56; and placebo 61,900 copies/mL, n=25; p=0.040) corresponding to a 0.44 log reduction. [Viral load set point was defined as the mean of the last two VL measurements prior to cART resumption or at termination of the treatment interruption period i.e., week 52].

Pre-ART VL values were available for 63 of the participants that remained off cART for 6 months (Vacc-4x n=45, placebo n=18). These correspond to historical viral load values taken within 6 months of cART initiation. There was a statistically significant reduction in median VL set-point (24,150 copies/mL) compared to pre-ART values (60,470 copies/mL) in Vacc-4x participants (n=45) (0.40 log reduction; p=0.0001). In contrast, the difference was not statistically significant for the placebo subgroup (n=18) where the VL set-point (median 50,400 copies/mL) returned to approximate pre-ART levels (52,731 copies/mL).

In subjects that completed a 6 month treatment interruption, an increase in proliferative assay responses over time to Vacc-4x antigens was observed in both CD4 and CD8 T-cell populations in the Vacc-4x group compared to placebo. ELISPOT responses to HIV p24 Gag (in the regions encompassed by Vacc-4x) were also measured. ELISPOT responders had a statistically significantly lower viral load set point in the Vacc-4x group than ELISPOT responders in the placebo group (Median 13,425 copies/mL Vacc-4x (n=32), 76,600 copies/mL placebo (n=15), p=0.022).

Vacc-4x was found to be safe and well tolerated in the intention to treat population (ITT) (n=135).

Vacc-4x Further Trials and Analysis

33 patients from the trial are currently enrolled in the Company’s Phase II Vacc-4x Reboost trial which investigates whether, upon booster immunizations, the viral load can be reduced even further on a second treatment interruption. The trial expects to read out Q1 2014.

Bionor Pharma has previously announces that a further exploratory ad hoc analysis of the Vacc-4x Phase II trial, identified anti-C5 antibodies as potential biomarker for the Company’s lead vaccine candidate Vacc-4x. Biomarkers may predict how well an HIV infected patient will respond to Vacc-4x. Response to Vacc-4x was defined as the reduction in viral load following a 6 months scheduled interruption of standard HIV treatment (ART) compared to the subjects’ historic viral load values (pre-ART values).

The analysis showed that patients more likely to respond to Vacc-4x, or responders, were characterized by pre-existing high levels of anti-C5 antibodies prior to Vacc-4x vaccination in the 2010 study. In conjunction with developing Bionor Pharma’s second HIV vaccine candidate, Vacc-C5 (Phase I), a test to quantify the presence of antibodies to C5 and gp41 was developed. Vacc-C5 is a peptide construct corresponding to the C5 region of the gp120 protein plus a minor part of gp41 in HIV.